- Research
- 15/12/2025
Home stretch | Cancer cells under the supermicroscope
TU/e researcher Marrit Tholen makes the invisible visible: using a super-resolution microscope, she examines nanoparticles and cancer cells down to the tiniest detail. Her PhD research shows how nanomedicines and vaccines can be delivered more precisely and reveals that real patient cells differ completely from standard laboratory cell lines.
During her master’s research, Marrit Tholen discovered her passion for microscopy. Under the guidance of Professor of Bio-Organic Chemistry Jan van Hest, she tried to count how many antibodies were attached to a nanoparticle.
In the process, she got a taste of the work done by Lorenzo Albertazzi’s group, which studies biological and synthetic materials at the single-molecule level—including nanoparticles. Tholen was captivated by the stunning images and the collaborative atmosphere, realizing that microscopy suited her perfectly.
After graduation, she took the initiative to ask Albertazzi if there might be a suitable PhD position for her. Her assertiveness paid off: she was invited to apply and began her PhD—right at the start of the COVID-19 pandemic.
Delivering to the right address
Tholen’s PhD focuses on nanoparticles, tiny packages that can deliver drugs or genetic instructions to specific cells. A similar principle is used in COVID-19 vaccines: the mRNA is packaged in lipid bubbles that carry it to the right place in the body, prompting cells to temporarily produce the spike protein so the immune system learns to recognize it as foreign. “It’s basically a tiny ‘DHL package’ traveling through your body,” Tholen explains.
She studied how these packages are structured on the outside and how to design them so they deliver their contents precisely to the right cells. “You can attach antibodies so specific cells recognize them. It’s like a barcode that the correct cell reads, letting the package enter only there,” she says.
This targeted delivery makes vaccines or medicines more efficient, with fewer side effects—especially important for chemotherapy, where the drugs otherwise attack the entire body, causing hair loss, nausea, and other side effects.
A cute black box
“The first goal of my research was to use super-resolution microscopy to see exactly what’s happening on the surface of nanoparticles,” Tholen explains. “Under a regular microscope, you just see a blur. Super-resolution microscopy lets you see precisely how many antibodies are on the nanoparticles and how they’re positioned.”
Working with this special supermicroscope was a completely new experience. “It doesn’t look like a regular microscope at all,” she says, showing the device in the lab. “It’s more like a cute black box.” Instead of looking directly into the microscope, everything is observed live on a computer screen. Tholen spent long hours studying nanoparticles in exquisite detail.
An antibody consists of a stem and two “arms,” forming a Y-shape. The arms bind to target cells, while the stem activates the immune system. If the antibody is attached to the nanoparticle with the stem facing outward, it’s cleared faster; if the arms face outward, it binds primarily to target cells.
Tholen compares it to a doorbell: receptors on the cell surface act like doors that an antibody can push to open. Press it correctly, and the door opens, letting the nanoparticle in. Press it wrong, and nothing happens. She studied which design rules allow nanoparticles to communicate optimally with cells.
The showpiece
After studying nanoparticles, Tholen turned to the cells themselves—especially cancer cells. Receptors on the cell surface aren’t static; they are constantly moving. The hypothesis is that this movement reflects underlying biological processes and influences how patients respond to therapy.
Together with Catharina Hospital, she set up a study with leukemia patients. Leukemia cells travel through the blood, making them easier to examine under the microscope. After a bone marrow puncture, these cells are usually discarded. “But that ‘waste’ is perfect for research,” Tholen realized.
This became the showpiece of her thesis. “It was the first time in the world that super-resolution microscopy was used to study receptor movement in live patient cells,” she says.
Technically, it had long been possible, but it requires immense effort: thousands of moving cells must be studied, massive amounts of data collected, and then analyzed. “It takes hours and hours at the microscope, followed by intense statistical analysis to make sense of it,” she explains.
Painstaking work
Tholen considered the painstaking work worth it: she fully committed herself, mapping the cell material from ten patients over countless hours in the lab. In the process, she discovered that each patient has a unique “fingerprint” of receptor movements.
“It’s something for future research to explore in detail, but at least we can now study the receptors on the surface of cancer cells in patient samples. That’s a big step,” she says. Ultimately, this could help doctors with diagnostics and choosing the right treatment.
Different bouquets
Her key message to scientists: cell lines—genetically identical cells grown in labs—bear little resemblance to real patient cells. “What you measure in the lab may not be relevant for the patient.” She uses a metaphor: patients are like bouquets with different flowers.
“For example, cell lines might contain only daisies, but patient bouquets have many types of flowers. Measure the cell lines ten times, and you get the same result each time. Measure patient cells ten times, and you get different bouquets each time, with different flowers, colors, and scents.”
Her research advocates for studying real patient material and developing better models. “Maybe that doesn’t apply to every disease, but for leukemia, it does. There are multiple types of cells involved, whereas a cell culture contains only one type. I’m thrilled we could demonstrate that, and I’m proud of it.”
Building your own microscope
Beyond her research, Tholen also completed a “PhD 5,” an extra year focused on education. “During those five years, I spent a lot of time shaping education here at TU/e,” she says. She developed a Challenge-Based Learning course where students built their own microscopes.
“Microscopes are expensive, so you can’t provide one for each of the sixty students,” she explains. "But you can 3D-print the parts and assemble a microscope, almost like building with Lego blocks.” It’s much cheaper—about eighty euros—and building it yourself gives students a deeper understanding of how optical components work and the physics behind them.”
“They have to adjust and manipulate things themselves, like the distance between lenses,” she adds. “Doing it yourself shows you cause and effect: if I do this, then that happens. It’s a totally different experience from just turning on a ready-made microscope and endlessly clicking until the image is sharp.”
PhD in the picture
What’s on the cover of your dissertation?
“There’s a whale on the cover. Although a whale has far more cells than a human, it rarely gets cancer—a phenomenon known as Peto’s paradox. With a super-resolution microscope, we’re basically looking inside the whale and seeing antibodies, cells, and even a tiny microscope.
In my research, I used proteins as markers to visualize cell structures. Many of these proteins come from flowers, like the daffodil. That’s why—and also to reference the metaphor of the flower bouquet—the floral motif appears throughout the dissertation. You also see a diver representing the researcher, and the bubbles he exhales are a nod to the nanoparticles.”
How would you explain your research at a birthday party in one sentence?
“I study what cancer cells look like, down to the tiniest details, using a special super-resolution microscope.”
How do you blow off steam outside the lab?
“I enjoy being creative. All the images in my dissertation were made by me using a technique called cyanotype. You place an object, like a flower, on paper coated with light-sensitive chemicals. When exposed to sunlight, the paper turns blue everywhere except under the object, leaving a kind of blueprint.”
What advice would you give your younger PhD self?
“Don’t stick too rigidly to the original plan. Serendipitous discoveries can lead to something much more beautiful and interesting. I started with nanoparticles and ended up studying cancer cells—which became the most important contribution of my dissertation.”
What’s the next chapter?
“That’s still uncertain. I have an offer from a university I’m considering, but I definitely want to continue with clinical studies and microscopy—that’s what really captured me. Sometimes you see something for the first time, something no one else in the world has ever seen. It’s a magical moment. When I first measured patient material, I was practically jumping in my chair, eager to share it with everyone.”
This article was translated using AI-assisted tools and reviewed by an editor.
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